Clinical interest of KRAS mutation detection in blood for anti-EGFR therapies in metastatic colorectal cancer

Abstract

a series of 59 metastatic colorectal cancer (MCRC) patients treated with cetuximab-based chemotherapy (CT), that KRAS mutation was highly predictive of treatment resistance and that progression-free survival was significantly increased in wild-type KRAS compared with mutant KRAS patients (Di Fiore et al, 2007). All the studies published so far have unambiguously confirmed that the presence of somatic KRAS mutation is indeed highly predictive of resistance to anti-EGFR antibodies in MCRC patients (Lièvre et al, 2006(Lièvre et al, , 2008Benvenuti et al, 2007;Frattini et al, 2007;Khambata-Ford et al, 2007;De Roock et al, 2008). Moreover, a large randomised controlled trial on panitumumab integrating KRAS genotyping has recently shown that, among 208 patients receiving panitumumab, 0 out of 84 mutants and 21 out of 124 (17%) wild-type patients were, respectively, responders (Amado et al, 2008). Therefore, KRAS genotyping should now be performed on a routine basis in patients with MCRC. In most of these studies, KRAS genotyping has been performed on primary colorectal tumours, whereas anti-EGFR antibodies are used to treat the metastatic disease. This strategy might, at least in certain circumstances, present two limitations. First, systematic KRAS genotyping in MCRC patients might be hampered in the future, at least for some patients, by the difficulty of obtaining tumour samples suitable for molecular analyses (and this might limit the use of anti-EGFR antibodies). Second, considering the genetic heterogeneity of colorectal cancers, the absence of detectable KRAS mutations in the primary tumour cannot formally exclude the presence of a KRAS mutation in metastases. For these two reasons, we think that detection of KRAS mutation in the blood of patients with MCRC may have a clinical interest in the context of anti-EGFR therapies and we would like to highlight in this letter the potential interest of such a strategy. Although several studies have shown the presence of mutant DNA in blood from patients with colorectal neoplasia, only positive results are informative. Therefore, one should consider the development of combined tests indicating in blood, first the presence of tumour DNA, then the status of KRAS. In MCRC, hypermethylated DNA can be used as a blood tumour molecular marker. For instance, hypermethylation of the RASSF2 gene has frequently been detected in colorectal adenoma and invasive carcinoma (Park et al, 2007), and we found, in a series of 32 Figure 1 Detection of methylated RASSF2A promoter in the primary tumour (T), liver metastases (M) and plasma (P) from patients 1 and 2. For patient 2, T1 and T2 correspond to the right and left colon adenocarcinoma, respectively. Genomic DNA was modified by bisulphite treatment and amplified with primers specific of the methylated RASSF2A promoter. M, molecular marker; Un, unmethylated DNA used as a negative control; Met, methylated DNA, used as a positive control. The arrows indicate the 110 bp amplified product (A). Detection of a KRAS mutation in the plasma from...

Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls

“…Moreover, considering the difficulty in obtaining metastatic tissue, at least in certain patients, analyses on blood samples should be of significant clinical interest. 26 Our study illustrates that different mechanisms can lead to artefactual mutations, as previously reported. 13,17,27 First, these artefacts have been reported when PCR amplification is performed on low amounts of DNA: a nucleotide misincorporation occurring during the first cycle of PCR will then be homogeneously carried by all PCR molecules generated during subsequent cycles.…”

Oncogenic mutations as predictive factors in colorectal cancer

“…Some authors have shown that detection of KRAS mutations in the peripheral blood of mCRC patients is possible by the development of combining tests indicating in blood, first the presence of tumour DNA (circulating tumours cells), then KRAS status, with a highly significant correlation to KRAS mutations in tumours (Di Fiore et al, 2008;Yen et al, 2009). Moreover, it was reported in a series of 76 patients that those with KRAS wild-type circulating tumour cells had a better progression-free and overall survival when treated with cetuximab plus chemotherapy (Po0.0001) (Yen et al, 2009).…”

Application of COLD-PCR for improved detection of KRAS mutations in clinical samples

“…[6][7][8][9] These therapies are exclusively effective in tumors with wild-type KRAS. [10][11][12][13] In colorectal cancer patients, in particular, KRAS mutation testing has quickly become standard-of-care. 14 In the era of targeted therapy and personalized medicine, requests for KRAS mutation testing will increase, and are likely to do so exponentially.…”